Osteoporosis is a metabolic bone disease with low bone mass and abnormal skeletal microarchitecture that increases bone fragility and, consequently, fracture risk. The skeleton constantly turns over owing to the carefully regulated breakdown of bone by osteoclasts and the ensuing replacement of the missing bone by osteoblasts. Progressive bone loss, with eventual compromise of its structural integrity. is caused by differences in the relative rates of bone resorption and formation, with an excess of the former over the latter. Most available drug treatments for osteoporosis are anti resorptive, inhibiting bone breakdown without directly affecting bone formation. Their effectiveness is necessarily limited, because when bone resorption is reduced, the rate of formation eventually diminishes as well due to the coupling of resorption and formation. Recruitment of osteoprogenitor cells is the most important step controlling bone formation rate and is followed by their differentiation to mature, boneforming osteoblasts. A major goal of osteoporosis research is to develop effective anabolic agents that will enhance osteoblast recruitment, differentiation and/or their ability to form mineralized bone. Extracellular calcium (Ca++) exerts various direct actions on the tissues maintaining Ca++ homeostasis, several of which are mediated by the Ca++ sensing receptor (CaR) cloned in 1993. High Ca++ also has direct actions on bone cells, stimulating the proliferation and chemotaxis of preosteoblasts and their differentiation to osteoblasts actions that could contribute to the known timulatory effect of high Ca++. The preliminary data presented here provide evidence that osteoblast-like cell lines express the CaR. This proposal's overall goal is to prove that the CaR acts on osteoblasts and their precursors to mediate anabolic actions of Ca++ on bone. This work may also provide a foundation for the future development of better treatments for osteoporosis an important cause of morbidity and disability in the aging population worldwide that actually increase bone formation. The specific aims of the proposal are as follows: Aim 1, To show that the CaR mediates high Ca++ evoked chemotaxis and proliferation of preosteoblastic cells, Aim 2, To show that the CaR promotes alkaline phosphatase and osteocalcin expression in osteoblastic cells, which reflect CaR induced differentiation to a more mature phenotype, Aim 3, To show that the CaR enhances the deposition of mineralized bone in vitro by comparing bone formation by osteoblastic cells and calvaria from wild type mice and homozygous CaR knockout mice in culture; and Aim 4, To prove the CaR's role as an important contributor to bone formation in vivo by generating a mouse model with selective "knock out" of the CaR in osteoblasts.